Extremity trauma, accounting for the majority (>60%) of combat wounds, results in peripheral nerve injury (PNI). Despite the propensity of peripheral nerve for regeneration, PNI patients commonly achieve no useful degree of sensorimotor recovery and suffer severe neuropathic pain (NP). New therapeutic approaches to facilitate recovery after PNI aim to provide (1) adequate Schwann cell (SC) numbers and SC-released factors required for repair and/or artificial bridging of a severed nerve, and (2) extracellular matrix milieu that inhibits fibrous sar formation and promotes axonal growth. In the course of this VA Merit Review program, we pioneered studies implicating matrix metalloproteinase-9 (MMP-9) as a protease uniquely expressed in adult nerve only after PNI involved in suppression of SC division via activation of NRG1/ErbB-ERK mediated cell cycle arrest. Our exciting new data implicates catalytic MMP-9 activity within the first days of PNI as determinant to SC-mediated remyelination, and the development of NP. Pharmacological MMP inhibition (MMPi) immediately after PNI facilitates sensory nerve regrowth by enhancing the rate of SC mitosis and preventing the development of a fibrous scar. Purification of MMP-9 from the PNI site using gelatin-sepharose beads identified multiple MMP-9 isoforms, which may be targeted by selective and unique anti-MMP-9 inhibitors. We provide novel data implicating an endogenous MMP-9 inhibitor, TIMP-1, as mediator of cAMP- induced pro-regenerative program in DRG after PNI, able to promote outgrowth of DRG neurons. Our groundbreaking data implies the existence of TIMP-1/CD63 signaling in SCs, independent of MMPs. We also offer the first studies implicating MMP-14 in PNI, using a new, highly selective MMP-14 inhibitor. Our data suggests that MMP-14 regulates peripheral nerve regeneration by proteolysis of laminin, neuron-glial antigen 2 (NG2) proteoglycan and MMP-2. Using state-of-the-art and specialized molecular and cell biological tools, as well as neuropathological and behavioral techniques, we will characterize the mechanisms and therapeutic value of MMP-9 (Aim 1) and MMP-14 (Aim 2) regulation of SC and DRG neuronal function, and MMP- dependent and MMP-independent TIMP actions in PNI. With cutting-edge, selective MMPi reagents and strong Preliminary Studies supporting their use, we anticipate this program will provide novel mechanistic insights and targeted therapeutic strategies to improve PNI related to combat and other prevalent conditions amongst VA patients.